Stimulator of interferon gene (STING) is a critical adaptor
protein
that has a pivotal role in triggering inherent immune responses to
infection. STING-linked interferon production has been involved in
anti-inflammation, anti-infection, and antitumor immunity. Herein,
a series of amidobenzimidazole analogues as STING agonists were profiled
for potency and drug-like properties. By structure-based modification
and optimization based on mono-aminobenzimidazole (ABZI), analogues
with nanomolar STING agonistic activities were obtained. Among them,
compounds D59 and D61 significantly increased
the transcription of IFN-β and proinflammatory
cytokine CXCL10, as well as dramatically induced
the phosphorylation of STING downstream proteins in THP1 cells. Furthermore,
compound D61 exhibited favorable pharmacokinetic properties
and metabolic stabilities. In a CT-26 syngeneic mice-bearing tumor
model, D61 effectively inhibited tumor growth with good
tolerance when administered via intratumoral, intravenous, intraperitoneal,
and oral routes. This research on orally bioavailable amidobenzimidazole
analogues expands the diversity of chemical structures of agonists
for STING-mediated immunotherapy.